A clinical trial is a culmination of the several stages of a drug or medical device development program that begins with the discovery of a candidate molecule followed by preclinical toxicology studies in ex vivo, in vitro, and animal models. Once the candidate molecule shows promising results in these stages, the next step involves clinical studies on human subjects. Drug testing in humans is often the most lengthy and expensive phase of the drug development timeline, and therefore requires extensive effort and careful execution to maximize the candidate’s chances of success. In addition to scientific evaluation, clinical studies require approval by the United States Food and Drug Administration (US FDA), the regulatory authority in the United States to administer the experimental drug in humans as well as ship it across state lines. This approval comes in the form of an Investigational New Drug (IND FDA) application that is required to be submitted by sponsors, investigators, or research institutes to the FDA to commence studies on human participants. The following figure shows the various stages of the drug development program (Figure 1) marking IND submission on the timeline.

1. IND Data Requirements and US FDA Submission Process
Table of Contents
​ Why is an IND required?
​ There are two main types of INDs:
​ Commercial IND:
​ Research IND:
​ Emergency use IND:
​ When do I need to submit an IND?
​ IND content and format
​ Module 1-Regional and administrative information
​ Module 2-Summaries
​ Module 3-Quality
​ Module 4-Nonclinical study reports
​ Module 5-Clinical study reports

2. ​ IND Submission Process to the US FDA
​
A clinical trial is a culmination of the several stages of a drug or medical device
development program that begins with the discovery of a candidate molecule followed
by preclinical toxicology studies in ex vivo, in vitro, and animal models. Once the
candidate molecule shows promising results in these stages, the next step involves
clinical studies on human subjects. Drug testing in humans is often the most lengthy
and expensive phase of the drug development timeline, and therefore requires
extensive effort and careful execution to maximize the candidate’s chances of success.
In addition to scientific evaluation, clinical studies require approval by the United States
Food and Drug Administration (US FDA), the regulatory authority in the United States to
administer the experimental drug in humans as well as ship it across state lines. This
approval comes in the form of an Investigational New Drug (IND FDA) application that is
required to be submitted by sponsors, investigators, or research institutes to the FDA to
commence studies on human participants. The following figure shows the various
stages of the drug development program (Figure 1) marking IND submission on the
timeline.
Figure 1. Schematic representation of drug development stages

3. Why is an IND required?
The IND is a comprehensive document that contains all the information gained from
preclinical and other studies in an organized format. The FDA reviews and makes the
decision to support further clinical studies from information in the IND that ultimately
forms the basis of marketing approval. INDs can be submitted at any phase during
clinical development to protect the safety and rights of subjects (Phase I) and to assure
adequate scientific evaluation of the drug’s effectiveness and safety (Phase II and III).
The Code of Federal Regulations CFR Title 21. Part 312 Investigational New Drug
Application contains information on INDs as well as their content and format and should
be reviewed thoroughly by sponsors or investigators prior to submission of an IND
application.
There are two main types of INDs:
● Commercial IND:
These are submitted by sponsors with the intent to commercialize the product at a later
stage.
● Research IND:
These are submitted by investigators or research institutions that do not intend to
commercialize the product.
● Emergency use IND:
Allows FDA to authorize the use of a drug in an emergency for which there is no
comparable treatment and that does not follow the exact format for the submission of
an IND according to 21 CFR Section 312
When do I need to submit an IND?
An IND should be submitted when planning to test a new drug in humans, when
planning to use an approved drug for an indication that has not been in the approved
labeling, when administered at a different dosage or by a different route of
administration, and when administered to a different population (unless certain
exemptions apply).

4. IND content and format
As of 2018, commercial use INDs must be submitted using the electronic Common
Technical Document (eCTD) format for acceptability by the FDA. The eCTD attempts to
harmonize marketing application structure and format in the US, EU, Japan, and other
countries adhering to International Council for Harmonisation (ICH) guidelines and helps
to save on paper and storage resources for documents.
INDs must contain information from three main areas: animal pharmacology and
toxicology, manufacturing information, clinical protocols, and investigator information
(Figure 2).
Figure 2. Information required for IND application

5. The eCTD format for the IND application contains 5 modules with specific information in
each (Figure 3).
The information that sponsors/investigators must submit in an IND application based on
21CFR 312.23 can be arranged in the CTD format as follows and should contain:
Module 1-Regional and administrative information
● Cover letter (FDA 1571)-sponsor details, phase of clinical trial, details about
clinical trial investigators and monitors, contract research organization (CRO)
details, IRB information
● Table of contents-introductory statement and general investigational plan, along
with information on previous human experience with the drug, investigational
marketing experience, and withdrawal information (if applicable) and plan for
investigation for one year
● FDA 3674-certification of compliance with requirements ClinicalTrials.gov data
bank
● Labeling-a copy of all labels and labeling to be provided to each investigator
● General Investigational Plan-contains information about the drug such as
structural formula, pharmacological class, dosage form and dose, route of
administration, and duration of trial
● Investigator’s brochure-contains information on the drug substance and formula,
summary of pharmacological and toxicological effects in animals and humans (if

6. known), summary of pharmacokinetics and biological disposition in animals and
humans (if studies), safety and effectiveness in humans from prior clinical
studies, possible risks, side effects, and precautions or special monitoring as per
expected adverse events based on prior experience with the drug or similar
drugs
● Module 2-Summaries
● Quality overall summary-this includes information about the drug
substance such as general information (nomenclature, structural formula),
manufacture, characterization, control of drug substance, reference
standards or materials, container-closure, and stability. Drug product data
must contain description, pharmaceutical development, manufacture,
control of excipients and drug product, reference standard or material,
container-closure, and stability.
● Nonclinical overview-the aim of this section is to present data to ensure
the safe use of the experimental drug in humans taking the
pharmacological, pharmacokinetic, and toxicological studies into
consideration.
● Pharmacology and pharmacokinetic studies: include
pharmacokinetic, toxicokinetic, and metabolism studies with the
methods used and analytical methods. Interspecies comparisons of
metabolism and pharmacokinetic parameters (AUC, Cmax), and
limitations for extrapolation of animal data to humans should be
discussed.
● Toxicology studies: onset, severity, and duration of toxic effects,
dose-dependency, reversibility (or irreversibility), and species and
gender differences. Genotoxicity, carcinogenicity, toxic signs,
causes of death, pathologic findings, pre-and postnatal toxicity,
safety of drug during pregnancy and lactation, and local tolerance.
Information Type of animal species, number of animals, route of
administration and dosages, duration of treatment, systemic
exposure should be included.
● Nonclinical summary-this includes written and tabulated summaries for
pharmacology, pharmacokinetic, and toxicology studies
● Pharmacology written summary and tabulated summary-primary
pharmacodynamics studies with other drugs in the class, secondary
pharmacodynamic studies summarized by organ systems, safety
pharmacology studies, and pharmacodynamic drug interactions. The
tabulated summary should contain information organized into sections
such as test system, method of administration, dose, species/strain,
gender, organ systems evaluated, etc.

7. ● Pharmacokinetics written summary and tabulated summary-method and
validation parameters for analytical procedure used for biological samples
in the study, absorption studies (in vitro extents and rate, BA/BE studies),
distribution studies (tissue distribution, protein binding, and placental
transfer studies), metabolism studies (metabolic pathways, pre-systemic
metabolism, P450 in vitro studies, enzyme induction and inhibition),
excretion studies (route and extent, excretion in milk), pharmacokinetic
drug interactions. The tabulated summary should include data under the
following headings species, vehicle/formulation, gender, dose, method of
administration, sample, analyte, assay, feeding condition, and sampling
time(s).
● Toxicology written summary and tabulated summary-single-dose toxicity
(species, route), repeated-dose toxicity (species, route, duration),
genotoxicity (in vitro mammalian and non-mammalian system, in vivo
mammalian system), carcinogenicity studies (long-term and short-term),
reproductive and developmental toxicity, local tolerance, and other studies
(immunogenicity, antigenicity, dependence, studies on
impurities/metabolites). Tabulated summaries should include the
species/strain, dose, route of administration, duration, observed maximum
non-lethal dose, and any noteworthy findings.
● Clinical overview-includes the product development rationale
(pharmacological class, target indication, current major therapies,
summary of ongoing and planned clinical studies), biopharmaceutics
(bioavailability issues related to formulations), clinical pharmacology
(pharmacokinetics: comparative PK related to intrinsic and extrinsic
factors, absorption, protein binding, metabolic pathways,
pharmacodynamics: mechanism of action and receptor binding, PK/PD
relationships, genetic differences, immunogenicity and clinical
microbiology), efficacy data (relevant patient population, study design, end
point(s), controls, statistical methods), safety (adverse effects and
monitoring, animal toxicology, overdose reactions), benefits and risks.
● Clinical summary-This section generally includes a tabulated summary
and comparison of individual studies related to biopharmaceutics and
analytical methods, clinical pharmacology, clinical efficacy, and clinical
safety.
● Module 3-Quality
This module contains chemistry, manufacturing, and controls data for the drug
substance and drug product.

8. ● Drug substance-general information (name, manufacturer), nomenclature (CAS
no., chemical name), structure (formula and stereochemistry), general properties
(pH/pKa, solubility, melting point, hygroscopicity, polymorphic form),
manufacturer’s name and address, description of manufacturing process and
controls (schematic flow diagram of process, raw materials, catalysts, solvents,
pH, critical steps, equipment, and operating conditions), control of raw materials
and solvents, control of critical steps and intermediates with acceptance criteria
process validation and evaluations, and manufacturing process equipment.
Specification criteria for drug substance, analytical procedures and validation
criteria, batches and batch analyses, and specification, reference standards and
materials, container-closure system description, and tabular listing of stability
protocol and studies
● Drug product-description of drug product, dosage, composition, type of container
system, drug substance, excipients, formulation development, results from in
vitro/in vivo comparative studies, physicochemical and biological properties
relevant to performance (pH, dissolution, particle size, flow properties, rheology,
potency, polymorphism, biological activity, etc.), manufacturing process
development (key validation parameters), container closure systems
microbiologic attributes, compatibility, batch formula, description of manufacturing
process and controls, process validation, excipient controls, stability data (stress
testing, photostability tests)
● Module 4-Nonclinical study reports
This section involves the organization of nonclinical study reports which include
pharmacology (primary and secondary pharmacodynamics, safety pharmacology, and
pharmacodynamic drug interactions), pharmacokinetics (analytical methods and
validation reports, absorption, distribution, metabolism, excretion, pharmacokinetic drug
interactions), toxicology (single-dose, repeat dose, genotoxicity, carcinogenicity,
reproductive and developmental toxicity, local tolerance, and other toxicity studies such
as antigenicity, immunogenicity, tolerance, immunotoxicity, etc.), and literature
references.
● Module 5-Clinical study reports
This section involves the organization of clinical study reports which include
biopharmaceutic study reports (bioavailability study, comparative BA/BE studies, In
vitro-in vivo correlations, bioanalytical and analytical methods), PK study reports
(plasma protein binding, hepatic metabolism and drug interactions, human biomaterial
studies), human PK studies (healthy subject and patient PK and tolerability reports,
intrinsic and extrinsic factor PK reports, population PK reports), human PD reports

9. (healthy subject and patient PK/PD reports), efficacy and safety reports (controlled and
uncontrolled clinical study reports,), reports of post-marketing experience, case report
forms and individual patient listings, and literature references.
IND Submission Process to the US FDA
An IND can be submitted by the sponsor/investigator at any phase of the clinical trial
stage but must be submitted prior to testing the experimental drug in human
participants. Figure 4 shows the steps for submission of the IND application to the FDA
using the eCTD format for electronic submissions.
Figure 4. Submission process to FDA using the electronic system for INDs
Following receipt of the eCTD submission to the FDA, the FDA has a 30-day period to
respond. The FDA can be in constant communication during this period to clarify any
concerns or doubts about the study. If there is no response from the FDA during this
window, the study can proceed. Otherwise, the FDA can place the study on partial hold
or clinical hold which can be due to inadequate data in the submitted IND or safety
concerns. It is the responsibility of the sponsor/investigator to address questions that
the FDA has posed and respond to these in a separate submission to the FDA. The
FDA can either lift the clinical hold allowing the clinical investigation to proceed, place
the study on partial hold (with certain restrictions), or continue the hold.

10. In addition to submitting the initial IND, the sponsor/investigator must keep the IND
current and submit any amendment to the IND such as protocol amendments, safety
reports, and IND annual reports.
Thus, a thorough and clear understanding of the requirements for an IND especially in
the eCTD format that is recommended by the FDA is necessary to maximize chances
for a smooth transition of experimental drug to the clinical trial phase. Furthermore,
reviewing the FDA submission process and maintaining contact with the FDA is
essential in updating the IND and protecting patient safety in case of any adverse
events or protocol deviations.
References:
● Understanding FDA Regulatory Requirements for Investigational New Drug
Applications for Sponsor-Investigators – PMC (nih.gov)
● M4E(R2): The CTD — Efficacy Guidance for Industry (fda.gov)
● Quality Overall Summary (QOS) in eCTD format (triphasepharmasolutions.com)
● Investigational New Drug (IND) Application | FDA
● Submit Using eCTD | FDA